Organismal and Genetic Networks in Drug Reward and Reinforcement

吸毒成瘾对与之作斗争的人的生活造成的破坏性影响以及对整个社会的社会和经济影响是惊人的。面对这一挑战，了解使人容易对可卡因（和其他药物）成瘾的生物学途径是研究界的首要任务。遗传背景被认为会影响一个人滥用药物的倾向，这一假设得到了动物模型研究、人类临床观察和 动物研究表明，小鼠近交系的行为差异，模型成瘾倾向。虽然没有动物模型可以概括人类药物滥用综合征的整个谱系，但确实存在动物模型来检查特定的药物相关行为。运动反应给药模型的初始敏感性药物的刺激作用。对精神兴奋剂表现出运动反应增强的啮齿动物在药物自我给药试验中也表现出更快的获得速度，这表明对可卡因的初始敏感性预示着成瘾的可能性。这项建议的目的是确定参与可卡因自发反应调节的遗传位点，作为药物敏感性的指标。我们的战略 利用近交系小鼠品系之间自然发生的表型变异和单倍型关联作图，这是一种定位复杂性状基因的遗传方法。此外，将在不同品系中检查涉及药物反应和成瘾的脑区域中的基因表达pAHerns以及可卡因的药代动力学性质，以鉴定可能导致表型变异的基因表达和药代动力学差异。

The devastating effects of drug addiction on the lives of those who struggle with it, and the social and economic implications for society as a whole are staggering. Faced with this challenge, understanding the biological pathways that predispose individuals to addiction to cocaine (and other drugs) is a top priority in the research community. Genetic background is thought to influence an individual's predisposition to abuse drugs and this hypothesis is supported by studies in animal models, by clinical observations in humans, and by animal studies showing mouse inbred strain differences in behaviors that model addiction liability. While no animal model exists that recapitulates the entire spectrum of the drug abuse syndrome in humans, animal models do exist to examine specific drug·related behaviors. Locomotor response to drug administration models initial sensitivity to the stimulant effects of the drug. Rodents that exhibit increased locomotor response to psycho stimulants also show faster rates of acquisition in drug self·administration assays, which suggests that initial sensitivity to cocaine predicts liability to addiction. The goal of this proposal is to identify genetic loci involved in the regulation of cocaine locomotor response as an indication of drug sensitivity. Our strategy takes advantage of naturally occurring phenotypic variation between inbred mouse strains and haplotype association mapping, a genetic approach for mapping complex trait genes. In addition, gene expression paHerns in brain regions involved in drug response and addiction as well as pharmacokinetic properties of cocaine will be examined across strains to identify gene expression and pharmacokinetic differences that may contribute to phenotypic variation.